Allergic asthma and rhinitis, atopic dermatitis (AD), urticaria and gastrointestinal allergy, are common diseases of infants and children. It was recently estimated that 14% of children suffer from AD, 8% from food allergy, and 12% from asthma [1,2]. The cumulated incidence of these diseases in adolescents has been estimated between 25-35%, while the prevalence is about 20% [3]. The phenotypic expression of these illnesses varies extensively, being very mild in some cases, severe in many, and even life threatening in others. Specific IgE antibodies to foods and positive challenge tests to a number of food allergens are frequently present in children with these disorders. Cow’s milk (CM) appears to be the most common offending food both in gastrointestinal (vomiting, diarrhea, etc) and in cutaneous manifestations (urticaria and AD). About 0.5-7% of infants suffer from more or less adverse reactions to CM [4].

Babies particularly of atopic parents are at high risk of developing atopic diseases; therefore they are defined as at-risk babies [5-7]. Atopy can interfere with a child’s life at any age level, with varying severity. Intractable diarrhea due to CM allergy (CMA) and AD are the most frequent in infants, where the clinical manifestations are more severe than in older children. Respiratory allergy and bronchial asthma can be serious illnesses in younger as well as in older children. The desire to understand the multifaceted problem of atopy has stimulated the clinicians’ and academicians’ imagination for decades. Therefore interest has been focused on methods for the prediction and prevention of atopy [5-9]. Prevention of IgE-mediated diseases relies on the skill necessary to overcome the natural forces unceasingly working to sensitize humans to produce IgE antibodies. The phenotypic expression of allergic disease ensues from an elaborate interrelationship between the atopy-prone genetic constitution of a child and the experienced environment that surrounds it.

Prevention of atopy could potentially be met by selectively interfering with the genetic and environmental factors that appear to be responsible in concert for the final phenotypic expression of atopy. Human milk has been for centuries the only way of feeding human neonates. Since the beginning of this century CM formulas have become a common breast milk substitute when mother’s milk was not available. During this century and especially in the last decade other formulas have been developed in order to reduce the antigen load and therefore the risk of sensitization. In this paper we will briefly summarize recent data on the environmental factors triggering atopy. In addition, we will report recent knowledge on atopy prevention, also reviewing the so-called hypoallergenic formulas.

Prediction of atopic disorders is an important step and should be carried out by examining both genetic factors and neonatal conditions. It has been known for centuries that heredity plays an important role in the development of atopy. A child with a negative family history still has about a 5-15% risk of developing atopy. However, children with a parental history of atopic disease are at higher risk for the development of atopic symptoms. It has been found that if one parent is affected, the chances of an offspring being affected vary between 20 and 4O%. If both parents are affected the figure increases up to 40-60%, and 50-80% if both show the same allergic manifestations. The risk of atopy in children who have an allergic sibling ranges between 25 and 35% [3,10].

The importance of genetic factors is also demonstrated by other data:

children with positive family history for atopy develop
allergic symptoms earlier than those with a negative family
history [11],

The higher the incidence the higher the number of
affected subjects in the same family [3].

Notable differences exist in the so-called predisposition
to atopic diseases, and further study appears to be necessary
to better delineate the role played by genetic factors in the
development of such disorders. In many allergic patients total
serum IgE levels are found to be elevated, and it has been shown
that a high total serum IgE level in infants is often associated with
the subsequent development of atopic symptoms. Therefore,
it was proposed that the measurement of IgE by PRIST testing
in infants or at birth would have a predictive value in the atopy
development. Several investigators have demonstrated that the
risk of developing atopic diseases was very high when the cord
IgE level was above 0.5 IU/ml [5,8,9,12]. Our data shows that a
newborn can be considered at risk for atopy when the cord IgE
level is above 0.8 IU/ml [5]. We have also shown that neonates of
non atopic parents (0.032 + 0.87 IU/ml in the not atopic vs O.295
+ 5.12 IU/ml in the atopic newborns, p < 0.005) [5].

Recent prospective studies have shown that the most
accurate predictive results are obtained when family history and
cord IgE levels are evaluated together [9,12]. The notion that a
neonate is at risk either by familial history or because of high
total IgE levels or from both causes may help it to better handle
the difficulties usually associated with a prevention program.
Recent personal data obtained from a series of preterm babies
of different gestational ages failed to show any significant
differences in total IgE levels according to gestational age [13],
thus suggesting that IgE synthesis is not increased during the
last months of gestation. It has been long known that a series
of prenatal, neonatal and environmental factors such as season
birth, home exposure to pets and tobacco smoke, viral infections,
and dietary factors can be important in the phenotypic
expression of atopy. We review hereafter the most important
features of these factors.

Several studies have suggested that infections during
pregnancy and food or drugs administered to pregnant women
are likely to lead to an increased risk of developing atopic
disease in babies. It has been recently reported that the IgE
concentration was higher in cord blood if the pregnant mothers
had been administered progesterone. However, these elevated
levels were not associated with an increased development of
atopic disease in the infants, nor were newborn IgM levels
related to subsequent allergies [14]. Can a baby be born allergic?
Although the research in this field is scarce, some experimental
and clinical observations have shown that the sensitization can
occur during fetal life. As early as 1928, Ratner demonstrated
intrauterine sensitization to CM proteins in Guinea pigs, and
speculated on analogous sensitization in humans [15].

Subsequently, it was found that IgE synthesis occur in
utero as early as the 11th week of gestation [16]. It was also
demonstrated that the fetus is capable of producing specific IgE
antibodies to food allergens that were ingested by the mother
during pregnancy. Antibodies to CM and soybean proteins have
been detected in both the amniotic fluid and cord blood [5,17].
Since the mothers had no antibodies to these allergens, it follows
that the antibodies had been synthesized by the fetus. It was
therefore recommended to atopic women not to ingest, during
pregnancy, excessive amounts of offending foods such as eggs
and CM [18,19]. Very recently a randomized study performed
in Sweden on a large population of pregnant women showed
that a strict CM and egg free diet during the last three months
of pregnancy had no effect on the development of atopy in the
babies [19,20].

Light and Wortley pointed out that a history of maternal
asthma, symptomatic during pregnancy, is associated with an
increased incidence of respiratory disease and/or jaundice in
newborns [21]. Another factor in prenatal life influencing the
development of atopy is the concentration of serum IgE in the
mother’s blood. Michel et al found that the more allergic the
mothers, the higher the IgE concentration in the cord blood of
their newborn infants [22]. If a mother had a serum-IgE level
of more than 100 IU/ml, the serum IgE level of her newborn’s
cord blood was significantly higher than that of newborns whose
mothers’ serum IgE levels were less than 100 IU/ml. Conversely,
Michel et al found that the IgE levels of the infants’ fathers did
not appear to influence the newborn’s cord blood IgE level [22].

The season of birth also seems to be a predisposing factor
in atopy sensitization, as first demonstrated by Soothill et al.
[23] who showed that the risk of developing a mite allergy was
dependent upon the month of birth. Subsequently a significantly
higher incidence of sensitization to pollens in children’s born
in the March-May period and to mites in children born in
the September-October period has been shown by several
investigators. However, other studies have failed to confirm
the above results [24]. We have examined 2532 children aged
1-14 years, all born in the Rome province. We showed that a
significantly high proportion of children born during the June-
September period had a Dermatophagoides pteronyssinus
allergy (p < 0.005), while those born during the March-May
period had a grass-pollen sensitivity (p << 0.005), in the Rome
province for the same age period of the children examined [24].

Certain features of a child’s prenatal history may
significantly affect his chances of developing bronchial asthma.
Accordingly a group of psychologists at the New York Hospital
studied three groups of children to verify this hypothesis. The
first group consisted of 30 children with bronchial asthma seen
for treatment in the Pediatric Allergy Clinic of the New York
Lying-In Hospital. Each of the other two groups consisted of
children without asthma selected from the birth records of the
above hospital. They were matched with the asthmatic group by randomly selecting two babies from the same obstetrical
unit. A greater frequency of neonatal complications was found
among the asthmatic children. These included complications
from either the mother or the baby in the prenatal period [25].
Therefore, a stressful birth significantly increases the chances of
a child subsequently developing bronchial asthma.

In early infancy, factors other than diet seem to “turn on”
allergic diathesis. A study was carried out in order to followup
the clinical impression of some pediatric allergists that
early surgery might increase the risk of developing asthma or
hay fever. In the first part of the study, 115 children who had
been operated on pyloric stenosis were followed-up and found
to have had an above-average prevalence of allergic disease. Of
those who had undergone such an operation, 20% developed
bronchial asthma, 21% developed hay fever and 36% developed
one or both of these conditions [26].

These figures were much higher than those found in
household interviews in the Rochester Child Health Study
investigation of a random sample of children 0-17 years of age in
Monroe Country, USA. The study showed that 3.4% of the random
sample of Rochester children had had asthma, 8.5% had had hay
fever, and 10.6% had had one or both of these conditions [27]. In
the second part of the study, Johnstone et al reported on 47 boys
who had a hernia repair and who were followed. They showed
similar results. Of those who had undergone a herniorrhaphy in
their first year of life, 34% developed asthma, 21% developed
hay fever and 55% developed either one or the other [26].

In the third part of the study, 202 children from the Rochester
Child Health Study, whose parents had reported that they had
had asthma or hay fever, were investigated for evidence of early
hospitalizations or surgery. Their parents reported significantly
more hospitalizations. For the boys less than two years of age
there were significantly more operations necessitating general
anesthesia than for non-asthmatic children of the same age from
the same random population group [26].

Another factor influencing the onset of asthma in early
infancy is home exposure to many potent allergens such as
mites, furred animal danders and pollens. Pets carry pollen
and dust on their fur. When it is hot, most pets drool saliva
since they do not sweat. This highly allergenic saliva dries and
becomes an important part of what we call “house dust” in the
home [28]. House dust mite appears to be the most common
offending allergen in asthma, and early exposure to this allergen
is associated with a significant increase of the risk of asthma
at the age of 11 [29]. Sporik et al concluded “we believe that
increased exposure to dust mites and other indoor allergen may
be a factor contributing to the recent increases in the morbidity
and mortality associated with asthma” [29]. Previous studies
have shown that early exposure to pets significantly influence the development of respiratory allergy to animal dander’s [30].

Morrison-Smith reported that atopy is less common in
“developing” than in “developed” countries [31]. In a study of
immigrants to Great Britain, he confirmed the lower incidence
of bronchial asthma in children of African origin who were born
outside Britain. Offspring of parents of African origin who were
born in England, however, had at least as high a prevalence of
atopic disease as non-African children. This suggests that the
difference in the prevalence of asthma in African children was
environmental rather than purely genetic [31]. Very recently we
have shown that the prevalence of AD was significantly higher
in Somali children living in Rome, in comparison with controls
living in Somalia (p < 0.001) and the age of weaning were
significantly lower in Somali children living in Rome. This data
again indicates that environmental factors may influence even
the onset of AD [32].

As mentioned earlier, viral infections frequently trigger
asthmatic attacks in children. During the last few years many
studies have reported that several of these viruses, including
respiratory syncytial virus (RSV), para influenza (types 1-3),
corona virus, adenovirus, and cytomegalovirus may contribute
to the development of allergic sensitization in the predisposed
children. In children of atopic parents, the allergic sensitization
accompanied by IgE synthesis manifested itself after viral upper
respiratory infections, in coincidence with the specific antibody
response to the virus. Increased levels of IgE antibodies have
been shown in various viral infections [33,34].

Previous studies have indicated that RSV-specific IgE
antibodies are more persistently present and that high RSV-IgE
titers are associated with increased concentrations of histamine
in patients affected by RSV infections [35,36]. In addition, RSV
and para influenza virus have the capacity to induce an IgEspecific
antibody response in the airway, the presence and
quantity of virus-specific IgE possibly being specifically related
to the severity of symptoms [37]. In recent studies, BALB/c
mice were infected intranasal with RSV and then exposed
either to ragweed or ovalbumin. The results suggested that
RSV infection can enhance the development of sensitization
and the magnitude of antibody responses to other inhaled
allergens found concomitantly in the respiratory tract during
acute infection [38,39]. There are several mechanisms by which
viral infections enhance the antibody-specific responses to
concomitantly inhaled allergens, thus favoring the development
of an atopic disease.

There could be alterations in the uptake and/or processing
of mucosal introduced allergens during virus-induced
inflammatory damage or preferential depression of IgE-specific
T-suppressor cells, resulting in increased IgE production. There
also could be enhancement of the IgE-mediated histamine release
associated with interferon production from the leukocytes of ragweed-allergic patients after viral infection, thereby altering
vascular permeability; and possibly, the result Beta-adrenergic
blockade would preferentially stimulate IgE antibody formation.
Moreover, viruses produce soluble factors that are chemo tactic
for basophils and that enhance histamine release from basophils
and mast cells [40].

Among the environmental factors favoring the development
of atopic disease, cigarette smoke plays a primary role. Evidence
is steadily accumulating that there is an important relationship
between parental smoking habits and atopic symptoms in
children. It has been observed that atopic symptoms start
earlier in the nonsmoking children of parents who smoke [11].
Moreover, immunologic studies corroborate these findings.
Reports of higher IgE levels in adult smokers [41] and in
infants of smoking atopic parents [42] support the view that
the immunologic abnormalities may be relevant. The issue of
whether smoking acts by irritating the respiratory mucosa [43],
which facilitates both the penetration of antigens and the spread
of infection, or by a direct action on the immune system has
yet to be resolved. Not only is tobacco smoke an irritant, but an
increasing body of evidence also indicates that it predisposes to
an increased susceptibility to respiratory viral infections.

This fits with recent data showing that adult smokers
contract influenza more frequently. Studies have also shown
a higher prevalence of recurrent respiratory infections in
children of smoking parents [43-45]. Since these affections are
asthmogenic, a vicious circle is started, especially in the winter
months in which a greater viral transmission is facilitated:
parents’ smoking ---> viral respiratory infections ---> asthma
in the child. As a result, only a drastic inhibition of smoking
can interrupt this cycle. All these results concur to stress the
importance of the environmental controls. Thus, there are
grounds to forbid smoking not only in the allergic child’s home,
but also in the house of any child at risk for development of
allergic disease. In addition, parents should not expose their
children to passive smoking in other confined spaces, such as
the family.

The possibility of preventing atopic diseases in high risk
babies has been confirmed by several groups of investigators and
we point out that in order to prevent atopic diseases in high risk
babies they should be subjected not only to dietary measures,
but also to environmental measures/ Our prevention program
includes 1) environmental and 2) dietary manipulations such as
follows:

Exclusive breast-feeding for the first six months of life;
total avoidance of cow’s milk, dairy products and eggs for
the nursing mothers; selected weaning after the 6th month
of life; cow’s milk and dairy products gradually introduced
after the 6th month and gluten shortly afterwards,

No smoking in the house; environmental controls for
the elimination of house-dust mite; no pets in the house;
day-care center attendance delayed to after the 3rd year.

As previously reported, several studies have suggested that
antenal sensitization to food antigens may occur; however this
phenomenon is quite rare. Antenal sensitization to different food
antigens may be explained not only by the transfer of nutrients via
the placenta, but also by the transfer of anti-idiotypic antibodies
from the mother to the fetus. In order to reduce the risk of antenal
sensitization, different approaches have been suggested, aimed
at modifying the mothers’ diet during pregnancy. It has been
shown that the complete exclusion of milk and dairy products,
eggs, fish, beef and peanuts during the pregnancy is associated
with a reduced prevalence of AD and also a significant reduction
in the severity score of the skin lesions [46].

However, two randomized studies failed to confirm the
protective effect of dietary measures during pregnancy [19,20].
We would like to emphasize that in these studies the dietary
measures were advised only in the last trimester of gestation
and the mothers were encouraged to drink a casein hydrolyzed
formula (Nutramigen) during the dietary restriction period. We
can hypothesize that the short period of dietary restriction and
the use of this formula may have influenced the negative results
(see section on hydrolysate formulas).

The preventive effect of breast-feeding on allergy
development in high-risk infants has been shown in several
prospective studies [6,7,47-49]. High risk babies should be
exclusively breast-fed for the first six months of life, since
human milk provides the infant not only with homologous
proteins which are non-allergenic but also with a number of
immunological factors which can prevent the absorption of
macromolecules. Therefore, the preventive effect might be
antigen non-specific

About 70 years ago American pediatricians documented
that AD in exclusively breast-fed infants could be related to
foods ingested by their mothers, and that the eczema cleared up
when the mothers avoided the offending food (s). In addition,
it was shown that exclusively breast-fed babies with AD had
positive skin tests to foods never previously ingested. It was thus
suggested that food antigens ingested by the mothers might pass
into the breast milk, thus sensitizing the babies. This passage
was first demonstrated by Stuart [50] who found that egg-whites
are present in breast-milk up to a dilution of 10 . The complete
exclusion of CM, eggs, fish and peanuts during breast feeding (six
months) significantly reduced the prevalence of AD [46].

A prospective randomized study [51] demonstrated that the
avoidance of CM, eggs and fish during the first three months of lactation was associated with a statistically significant reduction
in the prevalence of AD at the age of three and six months and
a significantly lower cumulative prevalence of atopic disease
at four years of age. We have investigated the sensitizing effect
via breast milk of a partially-hydrolyzed (whey proteins)
hypoallergenic formula. The formula was given to 39 nursing
“high risk” mothers (400 ml daily) during the lactation period
(six months) [52]. Another group of 39 nursing “high risk”
mothers, who consumed 400 ml of CM daily, served as control.
There was no significant difference in the cumulative incidence
of atopic diseases in the babies at one year of age according to
the mothers’ diet.

However, the prevalence of babies at 6 and 12 months with
specific IgE antibodies against the whey protein and with total
IgE antibody levels more than 2 SD from the normal values for
age were significantly higher (p = 0.02 ) in the group of babies
whose mothers received the hypoallergenic formula. This
preliminary study showed that a partially hydrolysate formula
not only still contains peptides which are able to sensitize highrisk
babies via breast milk, but it seems even more sensitizing
than CM [52]. Thus, it seems evident from the results of these
studies that it is mandatory to avoid allergenic foods such as
CM, eggs, fish and peanuts throughout the breast-feeding period
in order to prevent sensitization via breast milk. In addition, it
seems from our preliminary data that CM protein hydrolysate
formulas, when given to nursing mothers, may also sensitize the
babies.

We have shown in a multicenter study which was comprised
2.291 babies from several Italian maternity hospitals, that babies
fed breast and/or soy-milk, and whose parents strictly followed
the above shown environmental measures, had at one year of
age a lower prevalence of atopic diseases (5%) in comparison
with bottle-fed babies (13%). In addition, preventive measures
were able to significantly postpone the onset and reduce the
prevalence of allergy [53]. The results of this multicenter
study confirm our previous studies which have shown that the
prevalence of atopic diseases was significantly lower at age
four years in children whose parents followed the prevention
program [5-7,48].

Soy - protein formulas: Since 1929 soy protein formulas
have been used for feeding infants with CMA. They are well
accepted by most infants, and their nutritional adequacy is
comparable to that of CM formulas. As such, studies were
performed on infants fed a soy formula exclusively during
the first six months of life. They revealed no immunologic
abnormalities or increase in infection morbidity [54]. Regarding
the composition of soy protein formulas, they contain purified
soy protein, fat is a mixture of vegetable oils, and carbohydrates
are represented by maltodextrines, corn-starch or saccharose.
Supplements of the daily recommended vitamin requirements,
including vitamin D, are added so that problems, similar to those
found in premature infants, do not arise [55].

More recently, carnitine has been added to some soy
formulas in the same amount as that found in human milk to
supplement the limited quantities stored by infants. Carnitine, a
nitrogen quaternary base present in meat and CM, is synthesized
by the body from lysine and methionine. It allows the oxidation
of long-chain fatty acids so that they can be transferred from
the cytoplasm into the mitochondria, where they undergo
Beta-oxidation, producing energy. Infants cannot synthesize
adequate quantities of carnitine from lysine and methionine
because they lack the enzymes necessary for the biosynthesis.
As a consequence carnitine deficiencies have been reported in
infants fed soy formulas without added carnitine.

They are recognized by subclinical or clinical manifestations
resulting from the deficiency of the long-chain fatty acid
utilization [55]. Soy protein formulas are used for different
conditions including CMA, CM protein intolerance, lactose
and galactose intolerance and in the management of infants
with severe gastroenteritis. The use of such formulas for the
prevention of atopy is rather controversial. Some studies have
shown that soy formulas or breast-feeding supplemented with
soy formula for the first six months of life significantly reduce
the prevalence of atopic diseases [56,57]. In our studies, using a
soy protein formula when breast-milk was not available, we did
not see an increased prevalence of soy sensitization [6,7,48,58].

However, other studies failed to show any preventive effect
of soy formulas [59,60]. These contradictory results may be
explained by different factors. The number of babies studied
by Kjellman and Johansson [59] was very low, being only 23
subjects in the study. The babies studied by Chandra et al seemed
to belong to a very select atopic-prone study group, with specific
IgE and total cord blood IgE levels which were unusually high
[60]. There is no doubt that soy proteins can induce sensitization
and different allergic manifestations. However, during the last
decade soy allergenicity has been frequently emphasized in the
literature, without providing data on the true prevalence of soy
allergy in different allergic diseases.

Sampson has found that only 5% of 204 patients with AD
showed soy sensitivity has demonstrated by double-blind
placebo controlled challenge tests [61]. We have also confirmed
this demonstrating that only 4% of 143 children with AD showed
positive challenge tests to soy [62]. In addition, we reported a
study of 21 infants with AD due to CM hypersensitivity, where
a soy-protein formula was substituted in place of CM. Twenty of
these infants showed improved skin lesions with the soy-protein
formula [63]. Soy formulas are often poorly tolerated by infants
with chronic diarrhea. In fact, intolerance to soy proteins can be
a cause of chronic diarrhea often coexisting with CM intolerance.

Some investigators consider soy intolerance to be caused by
sensitivity to soy protein. However, neither a demonstration of
soy protein-sensitivity nor the mechanisms of this intolerance
have been clarified. It has been shown that a soy formula with
lactose was useful for feeding infants with chronic diarrhea and secondary multiple protein intolerance, including CM and
soy proteins [55]. In conclusion soy formulas are nutritionally
adequate and are well accepted by many infants. Many foods
such as cakes, biscuits, ice cream, desserts and beverages can
be made with soy protein formulas, thus offering children with
CMA a varied diet. Although soy proteins can be sensitizing, they
are less allergenic than CM proteins.

Hydrolysate Formulas: Hydrolyzed formulas have been
developed with the aim of decreasing or eliminating the
allergenicity of CM proteins. The use of these formulas is based
on the premise that pre-digested protein, when fed as amino
acids and peptides, provides nutrients in a non-antigenic form.
Thus, protein hydrolysate formulas have been classified as
“hypoallergenic”. These formulas are processed using two main
technologies: heat denaturation and enzymatic hydrolysis to
reduce the molecular weight of the peptides. The heat treatment
alters the conformational epitopes, while the enzymatic
hydrolysis affects the sequential determinants. These different
technical procedures are necessary for obtaining an acceptable
palatability.

However, with the reduction of the antigenicity (peptides
with very low MW) there is an associated reduction of the
palatability. The allergenicity of these formulas is dependent
on several factors such as the degree of digestion, the posthydrolysis
and the protein source itself. Extensively hydrolysate
formulas are considered the most hypoallergenic, whereas
partly hydrolysate formulas are considered less hypoallergenic
and even dangerous to children with CMA [64,65]. The MW
profiles of protein hydrolysates are an index of the extent of
hydrolysis. According to the protein source there are three types
of hydrolysate formulas: bovine casein (Alimentum, Nutramigen,
Pregestimil), bovine-whey (Alfa-Rè, Prophylac), and soy and
bovine-collagen (Pregomin). In addition, a bovine-whey partly
hydrolysate formula with lactose has been developed (Beba HA,
which is called HA in Italy and Good Start HA in US).

More recently, a partially casein and whey-protein
hydrolysate formula (Aptamil HA) has also been developed.
This product seems to be more adequate nutritionally because
it constats of 50% casein and 50% whey-protein. However, due
to the less extensive hydrolysis, this formula should be given
only for prevention and not for treatment of infants with CMA.
All these formulas are supplemented with vegetable lipids.
Alfa-Rè, Alimentum and Pregestimil also contain medium-chain
triglycerides. All hydrolysate formulas, excepted Beba HA, are
lactose free, and all contain small amounts of carnitine. They are
rather unpalatable (excepted Good Start) and for this reason the
compliance is poor.

Because hydrolysate formulas are nutritionally adequate,
infants generally gain weight until they refuse the formula
because of its bad taste. However, caution should be taken when
these formulas are given for prolonged periods because no data is available on nutritional assessment of infants fed exclusively
with such formulas for several months. The only data available is
from studies which have shown animal models that hydrolysate
formulas do not elicit an IgG response nor a cutaneous passive
anaphylaxis. In addition, infants fed casein hydrolysates during
the first three months of life do not show IgG antibodies to the
hydrolysate formula. This data strongly suggests that these
formulas are not antigenic. However, they do contain peptides
of MW greater than 2.500, which may elicit an IgE response in
predisposed infants [65].

We initially reported [66] 5 cases of infants, aged 3-8 months
(median 5 months) with an IgE-mediated CMA, who experienced
anaphylactic reactions when first fed a small amount of a whey
hydrolysate (Alfa-Rè). They all demonstrated positive skin test
and RAST to both CM proteins and Alfa-Rè. Subsequently, these
infants were all successfully fed a soy-protein formula without
further consequences. This data showed that whey-hydrolysate
formulas can trigger severe anaphylactic reactions in children
with an IgE-mediated CMA [66]. Later, other cases of anaphylactic
reactions were reported in infants with IgE-mediated CMA fed
hydrolysate formulas [67-69]. Confirmation of this is by a recent
study which demonstrated residual casein epitopes in all the
hypoallergenic formulas tested: Alfa-Rè, Pregomin, Beba HA
[65].

The above data strongly supports other studies [64] which
showed that antibodies raised against a CM formula recognized
epitopes displayed by peptides of other hydrolysate formulas:
Pregomin, Alfa-Rè, Nutramigen, Pregestimil. It was also shown
that hydrolysate formulas when injected into experimental
animals induced cell-mediated immunity and that crossreactivity
exists also between IgE antibodies to CM and peptides
of hydrolysate formulas, in this limb of the immune response.
Hydrolysate formulas contain protein fractions which result in
a specific IgE binding after incubation with serum samples from
patients allergic to CM [65].

In conclusion, although the proteins of hydrolysate formulas
have been processed by heat and enzymatic hydrolysis and
therefore contain peptides of lower MW than the native protein
source, the peptides still have allergenic capacity and can be
recognized by the cell-bound IgE antibodies of a child allergic
to CM. As shown by an elegant study, nine of fifteen children
sensitive to CM and with a positive histamine release from mixed
leukocytes also had a positive histamine release to at least one of
five tested hypoallergenic formulas [70].

According to recent studies, extensively casein hydrolysate
formulas are safer [71,72]. Generally, CM hydrolysate formulas
are well tolerated by infants with gastrointestinal symptoms
caused by CM intolerance and who do not have IgE antibodies
to CM proteins.

Several groups of investigators have used these formulas
(Nutramigen or HA) as breast milk substitute in high risk babies and although these studies have a short follow-up, the
results seems to be very encouraging [73-75]. A recent issue
of the Committee on Nutrition of the American Academy of
Pediatrics states that no published, well controlled, double-blind
studies exist to support the use of whey hydrolysates either for
prophylaxis or treatment of infants with CM hypersensitivity.
Limited clinical experience suggests that a whey hydrolysate
formula may be an acceptable alternative to CM and soy protein
formulas for infants intolerant, but not allergic, to CM [76]. We
conclude that partly hydrolysate formulas and whey hydrolysate
formulas should not be used in infants with IgE-mediated
CMA. Further studies are needed to investigate the nutritional
adequacy of hydrolysate formulas in babies fed exclusively such
formulas for several months.

Weaning: Another important dietary preventive measure is
selected weaning after the 6th month of life. This has been shown
to be a useful measure for atopy prevention [77]. However,
weaning is potentially dangerous for the high-risk baby. Special
care should be addressed when new foods are introduced into
these infants’ diet and offending foods such as eggs, fish, and
peanuts should be further postponed.

According to previous and recent studies, prevention of
atopic diseases in predisposed newborn babies seems to be
worthwhile. Environmental and dietary manipulations should
be addressed to “high-risk babies” in order to avoid, or postpone
the risk of sensitization, or to mitigate the clinical course of
the atopic disease once established.